Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide resulting in nutrient malabsorption which can lead to cognitive developmental defects in children. Mechanisms of pathogenesis in giardiasis are poorly understood, hindering efforts to both treat and prevent this disease. Data suggest that immune responses contribute to pathology by inducing shortening of the microvilli on intestinal epithelial cells that provide an enhanced surface area for nutrient absorption. Other studies indicate that changes occur in the tight junctions between epithelial cells resulting in increased epithelial permeability further hindering proper absorption of nutrients. This proposal will examine a novel hypothesis, that immune responses induce expression of a microRNA which reduces expression of key elements of the microvilli, resulting in both the reduction of microvillous surface area and increases in epithelial permeability. The role of immune responses in inducing production of this microRNA will be tested using genetically immunodeficient mice as well as by adoptively transferring select immune cells from infected mice to naive individuals. The role of the microRNA in pathogenesis will also be tested in vivo using mice which lack the gene encoding this microRNA and in vitro by overexpressing this transcript in intestinal epithelial cell cultures. Expression of microRNA targets, epithelial permeability and nutrient absorption will be analyzed both in vivo and in vitro. PUBLIC HEALTH RELEVANCE: Giardia is the most common protozoan cause of diarrhea in the US and is also considered a Biodefense Category B threat agent. The studies in this proposal will improve public health by examining how this infection causes nutrient malabsortion that can lead to defects in cognitive development. This information will provide new strategies for treating common diseases like celiac disease and inflammatory bowel disease as well as diarrheal diseases like Giardia.